Early exposure to antibiotics, resulting in microbial imbalance, exacerbates response to gluten, according to research published in The American Journal of Pathology

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Philadelphia, PA, October 8, 2015

Investigators interested in celiac
disease, a chronic gastrointestinal disorder caused by an immunologic response
to the ingestion of gluten, have wondered why only 2% to 5% of genetically
susceptible individuals develop the disease. Attention has focused on whether
environmental determinants, including gut microorganisms, contribute to the
development of celiac disease. Using a humanized mouse model of gluten
sensitivity, a new study in The American
Journal of Pathology found that the gut microbiome can play an important role
in the body’s response to gluten.

“Importantly, our data argue that the
recognized increase in celiac disease prevalence in the general population over
the last 50 years could be driven, at least in part, by perturbations in
intestinal microbial ecology. Specific microbiota-based therapies may aid in
the prevention or treatment of celiac disease in subjects with moderate genetic
risk,” explained lead investigator Elena F. Verdu, MD, PhD, Associate
Professor, Division of Gastroenterology, Department of Medicine, Farncombe
Family Digestive Health Research Institute, McMaster University, Hamilton, ON
(Canada).

Using mice that express the human DQ8 gene, which makes them genetically susceptible
to inflammatory responses to gluten, researchers compared immune responses and
pathology in the guts of mice that differed in their gut microorganisms. The
three groups were germ-free mice, clean–specific-pathogen-free (SPF) mice with microbiota free of
opportunistic pathogens and Proteobacteria, and conventional SPF mice that were
colonized with a mixture of microorganisms including opportunistic pathogens
and Proteobacteria. For example, the microbial composition of conventional SPF
mice included Staphylococcus, Streptococcus, and Helicobacter, but the clean SPF had none.

It is known that proliferation and
activation of intraepithelial lymphocytes (IELs) is an early hallmark of celiac
disease. Investigators observed that gluten treatment led to increased IEL
counts in germ-free mice but not in clean SPF mice. The gluten-induced IEL
response in germ-free mice was accompanied by increased cell death in enterocytes
(the cells lining the gastrointestinal tract) as well as anatomical changes in
the villi (the tissue protrusions lining the small intestine). The germ-free
mice also developed antibodies to a component of gluten, known as gliadin, and displayed
pro-inflammatory gliadin-specific T-cell responses. A non-gluten protein, zein,
did not affect IEL counts, indicating that the response was gluten specific.

Conversely, in the mice colonized
with limited opportunistic bacteria (clean SPF), the development of
gluten-induced pathology was prevented compared to germ-free mice or
conventional SPF mice with a more diverse microbiota. Interestingly, this
protection was suppressed when clean SPF mice were supplemented with an
enteroadherent E. coli isolated from
a patient with celiac disease.

Gluten-induced pathology (ie, increased
IELs in villi tips) was worse in conventional SPF mice than in clean SPF mice. To
test if the presence of Proteobacteria such as Helicobacter and Escherichia
in the conventional SPF animals affected the pathology, the investigators expanded
Proteobacteria in conventional SPF mice using an antibiotic (vancomycin) during
the perinatal period. Such expansion worsened gluten-induced pathology in
conventional SPF mice, as measured by the number of IELs, possibly due to the
presence of more Proteobacteria. “These studies demonstrate that perturbation
of early microbial colonization in life and induction of dysbiosis (microbial
imbalance inside the body), characterized by increased Proteobacteria, enhances
the severity of gluten-induced responses in mice genetically predisposed to gluten
sensitivity,” noted Dr. Verdu.

In an accompanying Commentary, Robin
G. Lorenz, MD, PhD, of the Department of Pathology at the University of Alabama
at Birmingham, cautions that the specific role of Proteobacteria should not be over
interpreted. Dr. Lorenz writes that these findings “implicate opportunistic
pathogens belonging to the Proteobacteria phylum in celiac disease; however,
this does not indicate that Proteobacteria cause celiac disease.” Instead, there
may be multiple potential mechanisms by which Proteobacteria enhance the
exposure and immune response to gluten or gliadin, suggests Dr. Lorenz.

Celiac disease affects approximately
1% of the North American population, although it has been estimated that 83% of
Americans with celiac disease are undiagnosed or misdiagnosed. According to the
National Institute of Diabetes and Digestive and Kidney Diseases, celiac
disease is an immune disorder in which ingestion of gluten, a protein found in
wheat, rye, and barley, triggers a series of responses that result in damage to
the villi lining the small intestine, which are critical for absorption of
nutrients. In addition to digestive symptoms (bloating, chronic diarrhea,
constipation, nausea, and vomiting), celiac disease can lead to failure to
thrive, slowed growth, and weight loss in children and anemia, bone or joint
pain, depression, headaches, and fatigue in adults. Other potential
environmental factors related to gluten sensitivity have been explored, such as
the timing of exposure to foods containing gluten or breast milk versus formula
feeding, but data are inconclusive to date.

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Notes for EditorsThis
research was supported a Canadian Institutes of Health Research grant 31 MOP#123282
to E.F.V., and partially by grants from the US National Institute of Health R01
32 DK67189 to B.J. and AGL2011-25169 from MINECO to Y.S. H.J.G. and J.L.M.
received New 33 Investigator Awards from the Canadian Celiac Association and
M.M. a grant from the FWF 34 Austrian Science Fund (Erwin Schrödinger
Fellowship, J 3418-B19). E.F.V. and M.J. hold.Canada Research Chairs.

This article and editorial appear online
ahead of The American Journal of Pathology, Volume 185, Issue 11 (November 2015) published by Elsevier.

Full text of this study and editorial is available to
credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com.

About
The American Journal of PathologyThe American Journal of Pathology, official journal
of the American Society for Investigative Pathology, seeks to publish
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